Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+ T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.

Clinical Pharmacology Sun Pharma Advanced Research Company Mahakali Mumbai 400093 India

Department of Cell Biology Johns Hopkins University Baltimore MD 21205 USA

Department of Dermatology Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Department of Internal Medicine Division of Hematology Oncology University of Iowa Iowa City IA 52242 USA

Department of Medicine Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Department of Neurology Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Department of Neuroscience Johns Hopkins University Baltimore MD 21205 USA

Department of Oncology Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Department of Pharmaceutics National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar 382355 India

Department of Pharmacology and Molecular Sciences Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Drug Metabolism and Pharmacokinetics Sun Pharma Advanced Research Company Savli 391770 India

In Vitro Biology Sun Pharma Advanced Research Company Savli 391770 India

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Prague 166 10 Czech Republic

Johns Hopkins Drug Discovery Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Medicinal Chemistry Sun Pharma Advanced Research Company Savli 391770 India

Preclinical Pharmacology Sun Pharma Advanced Research Company Savli 391770 India

Translational Development Sun Pharma Advanced Research Company Savli 391770 India

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PNAS Nexus. 2023 Jan 27;2(1):pgad016. doi: 10.1093/pnasnexus/pgad016. PubMed

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Discovery of Orally Available Prodrugs of Itaconate and Derivatives